Sayuri Sukigara

Delayed maturation and differentiation of neurons in focal cortical dysplasia with the transmantle sign: analysis of layer-specific marker expression.

Abstract Transmantle dysplasia is a rare type of focal cortical dysplasia (FCD) characterized by expansion of the cortex from the deep white matter to the surface and in which there is a FCD IIA or IIB pathologic pattern. To characterize possible mechanisms underlying this regional disorder of radial migrating cells, we studied the expression patterns of neocortical layer-specific markers using immunohistochemistry in surgical specimens from 5 FCD IIA and 4 FCD IIB cases in children. All neuronal cells expressed the mature neuron marker MAP2/2B but not the microglia markers Iba-1 and CD68. Some layer-specific markers showed distinct expression patterns. TBR1-positive, SATB2-positive, and FOXP1-positive cells were diffusely distributed in the cortex and/or the white matter. TBR1-positive and FOXP1-positive cells were generally more numerous in FCD IIB than in FCD IIA and were mostly in the cortical molecular and upper layers. FOXP1-, FOXP2-, and CUTL1-positive cells also expressed the immature neuron marker, Nestin/PROX1, whereas TBR1-, CTIP2-, and SATB2-positive cells only expressed MAP2/2B. These data highlight differences between FCD IIB and FCD IIA with more cells having the immature marker in upper layer markers in the former. By analyzing layer-specific marker expression patterns, we identified apparent neuronal maturation differences between FCD IIA and FCD IIB in cases of transmantle dysplasia.

Muscle glycogen storage disease 0 presenting recurrent syncope with weakness and myalgia.

Muscle glycogen storage disease 0 (GSD0) is caused by glycogen depletion in skeletal and cardiac muscles due to deficiency of glycogen synthase 1 (GYS1), which is encoded by the GYS1 gene. Only two families with this disease have been identified. We report a new muscle GSD0 patient, a Japanese girl, who had been suffering from recurrent attacks of exertional syncope accompanied by muscle weakness and pain since age 5 years until she died of cardiac arrest at age 12. Muscle biopsy at age 11 years showed glycogen depletion in all muscle fibers. Her loss of consciousness was gradual and lasted for hours, suggesting that the syncope may not be simply caused by cardiac event but probably also contributed by metabolic distress.

Imbalance of interneuron distribution between neocortex and basal ganglia: Consideration of epileptogenesis of focal cortical dysplasia

AIM The balance of excitation and inhibition of neurons and neuronal network is very important to perform complete neuronal function. Damage or loss of inhibitory γ-aminobutyric acid (GABA)-ergic interneuron is associated with impaired inhibitory control of cortical pyramidal neurons, leading to hyperexcitability and epileptogenesis. Ectopic neurons in the basal ganglia are to be one of the pathological features of epileptogenesis. In the present study, we investigated distribution of interneuron subtypes between neocortex and caudate nucleus. METHODS We performed immunohistochemistry of GABA, glutamic acid decarboxylase (GAD), calretinin (CR), calbindin (CB), parvalbumin (PV) and neuropeptide. We used surgical materials of four focal cortical dysplasia (FCD) cases, having lesions of neocortex and caudate nucleus, and eight age-matched autopsy controls. RESULTS The pathology showed three FCD IIa, containing dysmorphic neurons, and one FCD IIb, balloon cells. In the neocortex, the concentrations (each positive cell number/all cell numbers in the evaluated field) of GAD+, CR+ and CB+ cells were significantly lower in FCD than in controls. On the contrary, in the caudate nucleus those of CR+ and CB+ cells were significantly more in FCD than in controls. CONCLUSION The interneuron imbalance between the neocortex and basal ganglia may affect the epileptogenesis of FCD.

Abnormal maturation and differentiation of neocortical neurons in epileptogenic cortical malformation: unique distribution of layer-specific marker cells of focal cortical dysplasia and hemimegalencephaly.

Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are major causes of intractable epilepsy in children. The probable pathogenesis of FCD and HMG is the abnormal migration and differentiation of neurons. The aim of the present study was to clarify the abnormal cytoarchitecture, based on neuronal immaturation. Tissue samples were obtained from 16 FCD and seven HME patients, aged between 2 months and 12 years, who had been diagnosed as typical FCD and HME, following surgical treatment for intractable epilepsy. Paraffin-embedded sections were stained with the antibodies of three layer-markers that are usually present only during the fetal period, namely SATB2 (expressed in the upper layer of the normal fetal neocortex), FOXP1 (expressed in the 5th layer), and TBR1 (expressed in the 6th layer). In FCD, SATB2-positive (+) cells located in the middle and deep regions of FCD Ia and Ib, but only in the superficial region of FCD IIa and IIb. FOXP1+ cells diffusely located in the neocortex, especially the upper layer of FCD IIa and IIb. TBR1+ cells mainly located in the middle and deep regions, and also white matter. In FCD IIb, TBR1+ cells were in the superficial region. In HME, SATB2+ and FOXP1+ cells were found diffusely. TBR1+ cells were in the middle and deep regions. On the basis of continued expression of fetal cortical layer-specific markers in FCD and HME brains, the abnormal neocortical formation in both is likely to be the result of disrupted neuronal migration and dysmaturation. The expression pattern is different between FCD and HME.

Expression of Astrocyte-Related Receptors in Cortical Dysplasia With Intractable Epilepsy

Epilepsy is one of the major neurologic diseases, and astrocytes play important roles in epileptogenesis. To investigate possible roles of astrocyte-related receptors in patients with intractable epilepsy associated with focal cortical dysplasia (FCD) and other conditions, we examined resected epileptic foci from 31 patients, including 23 with FCD type I, IIa, or IIb, 5 with tuberous sclerosis complex, and 3 with low-grade astrocytoma. Control samples were from 21 autopsied brains of patients without epilepsy or neurologic deficits and 5 patients with pathologic gliosis without epilepsy. Immunohistochemical and immunoblot analyses with antibodies against purinergic receptor subtypes P2RY1, P2RY2, P2RY4, potassium channels Kv4.2 and Kir4.1, and metabotropic receptor subtypes mGluR1 and mGluR5 were performed. Anti-glial fibrillary acidic protein, anti-NeuN, and anti-CD68 immunostaining was used to identify astrocytes, neurons, and microglia, respectively. Most glial fibrillary acidic protein-immunopositive astrocyte cells in the brain samples from patients with epilepsy were P2RY1-, P2RY2-, P2RY4-, Kv4.2-, Kir4.1-, mGluR1-, and mGluR5-positive, whereas samples from controls and pathologic gliosis showed lower expression levels of these astrocyte-related receptors. Our findings suggest that, although these receptors are necessary for astrocyte transmission, formation of the neuron-glia network, and other physiologic functions, overexpression in the brains of patients with intractable epilepsy may be associated with activation of intracellular and glio-neuronal signaling pathways that contribute to epileptogenesis.

Pathologic Active mTOR Mutation in Brain Malformation with Intractable Epilepsy Leads to Cell-Autonomous Migration Delay

The activation of phosphatidylinositol 3-kinase-AKTs-mammalian target of rapamycin cell signaling pathway leads to cell overgrowth and abnormal migration and results in various types of cortical malformations, such as hemimegalencephaly (HME), focal cortical dysplasia, and tuberous sclerosis complex. However, the pathomechanism underlying abnormal cell migration remains unknown. With the use of fetal mouse brain, we performed causative gene analysis of the resected brain tissues from a patient with HME and investigated the pathogenesis. We obtained a novel somatic mutation of the MTOR gene, having approximately 11% and 7% mutation frequency in the resected brain tissues. Moreover, we revealed that the MTOR mutation resulted in hyperphosphorylation of its downstream molecules, S6 and 4E-binding protein 1, and delayed cell migration on the radial glial fiber and did not affect other cells. We suspect cell-autonomous migration arrest on the radial glial foot by the active MTOR mutation and offer potential explanations for why this may lead to cortical malformations such as HME.

Focal cortical myoclonus in rolandic cortical dysplasia presenting as hemifacial twitching

A 2-year-old girl presented with brief episodes of left hemifacial twitching. On ictal electroencephalography, repetitive focal spike discharges appeared at the right fronto-centro-temporal regions; these discharges preceded the onset of each twitch by 12 ms. Magnetic resonance imaging showed a linear abnormal signal intensity in the subcortical white matter at the right postcentral gyrus, where a cluster of dipole sources was detected by magnetoencephalography. These findings suggested that the patient had focal cortical myoclonus due to rolandic focal cortical dysplasia.

Effects of low-dose hydrochlorothiazide on urolithiasis and bone metabolism in severely disabled individuals: A pilot study

To clarify the effects of hydrochlorothiazide (HCT) on calcium metabolism in subjects with severe motor and intellectual disabilities (SMID), we examined four patients (16-48years old) with a history of urolithiasis and/or bone fracture and increased urinary calcium/creatinine ratio (U-Ca/Cr). U-Ca/Cr, blood markers of bone turnover, and bone-mineral density (BMD) were measured before and after administration of low-dose HCT (0.25-0.5mg/kg/day). Three months after the initiation of HCT, U-Ca/Cr decreased in all patients, but this effect was less evident at 9-18months. Bone-turnover marker of bone-specific alkaline phosphatase also showed a tendency to decrease, but BMD remained unchanged during the follow-up period. In SMID patients, HCT is beneficial for the treatment of hypercalciuria but its effects can be transient in certain cases. HCT may also ameliorate the increase in bone turnover, but its effects on the prevention of bone fractures remain uncertain. Hyponatremia is the most frequent and significant adverse effect of HCT, for which a close observation is mandatory in HCT application for patients with SMID.

13. Evaluation of language dominance in a child of intractable epilepsy with mental retardation

The Wada test has been a golden standard to evaluate the lateralization of language dominance before epilepsy surgery. However, this test has not been applied to going children, especially with mental retardation. Because it is an invasive test with risks of neurologic complications. Although some non-invasive alternatives, such as MEG, fMRI or NIRS are recently applied, there are a few reports of children. We performed three types of non-invasive procedures for language lateralization (NIRS, MEG and Dichotic listening test) as well as the Wada procedure by using very short-acting anesthesia in a child of intractable epilepsy with mild mental retardation before hemispherotomy. Each indicated that the language dominance is lateralized in the same hemisphere. Although there are many risks for Wada test in the introduction of catheter for restless children who can not follow directions, using very short-acting general anesthesia may allow them to diminish risks. In addition, the result that all of three non-invasive tests are in good concordance with Wada test, which suggests these non-invasive tests have a potential to substitute for Wada test even in young children. Further studies in pediatric patients with mental retardation are needed in order to confirm usefulness of these non-invasive methods.